Medicinal cosmetic lipoatrophy

ABSTRACT

Methods relating to local injections of corticosteroids are provided. More specifically intralesional injections of corticosteroids and preferably Triamcinolone and its derivatives are suitable to produce medicaments to be injected in the subcutaneous fat at deep levels to provoke cosmetic lipoatrophy of small fat deposits on the face and body.

CROSS REFERENCE TO RELATED APPLICATION

This application is for entry into the U.S. National Phase under §371for International Application No. PCT/BR2010/000059 having aninternational filing date of Feb. 3, 2010, and from which priority isclaimed under all applicable sections of Title 35 of the United StatesCode including, but not limited to, Sections 120, 363 and 365(c), andwhich in turn claims priority to Provisional Patent Application No.61/209,065 filed on Feb. 3, 2009.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to a composition comprising at least oneinjectable corticosteroid and a diluent, preferable an anestheticsolution, which is suitable for producing medicaments to diminish smallfat accumulations on the face and body by causing atrophy of the fatcells.

2. Description of Related Art

At present, subcutaneous accumulations of fat are treated by surgicalmeans through liposuction or direct surgical removal. For small fatdeposits, such those occurring with aging in some areas of the face,liposuction is too aggressive and is associated with the knowncomplications or risks.

Injectable drugs, such as phosphatidylcholine (PPC) and sodiumdeoxycholate, also known as lipodissolve agents, were also used in somecountries in the last few years (particularly in Brazil up to 2002),although there are no studies proving their safety and efficacy.Moreover, these drugs were also associated with severe side effects,including death in animals. (Paschoal, L H, Lourenço L, Ribeiro A, etal. Um alerta! Efeitos sistêmicos e teciduais da fosfatidilcolina emsuínos [poster]. Presented at 16° Congresso Brasileiro de CirurgiaDermatológica. Porto de Galinhas June, 2004)

US2005/0143347 describes a method for removing subcutaneous accumulationof fat as well as aqueous preparations comprising at least onephospholipid and/or at least one bile acid and a component assistingdegradation of fat such as riboflavin. An anti-inflammatory compound canbe added in the preparation.

The term “corticosteroids” means compounds from the adrenal cortex. Intechnical terms, corticosteroid refers to both glucocorticoids andmineralocorticoids (as both are mimics of hormones produced by theadrenal cortex), but is often used as a synonym for glucocorticoid.Glucocorticoids are a class of steroid hormones characterized by anability to bind with the glucocorticoid receptor (GR) and triggersimilar effects. Glucocorticoids are distinguished frommineralocorticoids and sex steroids by their specific receptors, targetcells, and effects.

Glucocorticoids have potent anti-inflammatory and immunosuppressiveproperties. This is particularly evident when they are administered atpharmacologic doses, but also is important in normal immune responses.As a consequence, glucocorticoids are indicated for the treatment ofmany diverse conditions, including allergies, autoimmune diseases andinflammatory disease like asthma (New England J Med 2005; 353:1711-23).

Corticosteroids can be used topically, orally and by injections.Injectable corticosteroids currently used in medicine include theshort-Acting injectable corticosteroids such as cortisone andhydrocortisone; the intermediate-Acting Injectable corticosteroids suchas Prednisone, Prednisolone tebutate, Triamcinolone andMethylprednisolone its derivatives such as methylprednisolone acetate;the long-Acting corticosteroids such as Dexamethasone and itsderivatives such as Dexamethasone sodium phosphate and Betamethasone itsderivatives such as betamethasone dipropionate, beta-methasone disodiumphosphate and betamethasone acetate, and others.

Triamcinolone and other systemic corticosteroids have stronganti-inflammatory effects and this explains the large use of thesecompounds in medicine. At Medline, more than twenty-five thousandspapers are published on injectable corticosteroids and more than fivethousands papers on triamcinolone are published. Injectablecorticosteroids are usually commercialized in stable aqueous suspensionand are also described in the Patent Applications or patents such asU.S. Pat. No. 6,395,294 owned by Triesence (exploitation by Alcon) untilJan. 13, 2020 for Triamcinolone acetonide in intravitreal injectableform;

Triamcinolone acetonide injectable suspension USP (Kenalog®-40Injection, Bristol-Myers Squibb Company, Italy) is a syntheticcorticosteroid designed to provide systemic immunosuppressant andanti-inflammatory effects, as well as other intralesional or sublesionallocal effects for various skin diseases and conditions. The drug isstable at room temperature and must be shaken well before using.

Triamcinolone and/or other injectable corticosteroids are commonly usedin dermatology for intralesional injections, as well as in otherspecialties and diseases, such as for joint inflammation and pain.Intralesional corticosteroids injections release a high concentration ofthe drug directly on the action site, with minimal systemic absorption.These drugs are considered very safe, low cost and efficient for anexpressive number of diseases and conditions, for patients of differentages. Few applications and low doses are considered extremely safe, alsofor patients presenting severe diseases.

The aging process is caused by intrinsic and extrinsic aging, as well aschanges in hard and soft tissues. Muscular hyperactivity causes dynamicwrinkles and is currently being treated by botulinum toxins; the lossesin hard and soft tissues are currently being treated by fillers; thesurface alterations are being treated by ablative and non-ablativetechniques, as well as by topical retinoids and other activeingredients. There are no currently medical approved drugs forage-related fat accumulation. It is reported that fat pads like thoseoccurring under the eyes, on the abdomen or on the hips of overweightpeople shrink, and there are said to be esthetic improvements in theappearance of the treated people, if these people received subcutaneousinjection of Lipostabil® N I.V. (Patricia Guedes Rittes, The Use ofPhosphatidylcholine for Correction of Lower Lid Bulging Due to ProminentFat Pads, Dermatol. Surg. 2001; 27: 391-392). Residual small fatdeposits are also common complaints after liposuction.

SUMMARY OF THE INVENTION

In the attempt to find effective compounds for nonsurgical removal ofsubcutaneous accumulations of fat, it has now surprisingly been foundthat subcutaneous administration of Triamcinolone and/or othercorticosteroids, at low doses and few applications, which have to datebeen used for many diseases and conditions, also lead to a safe andeffective regression of small fat deposits in the face and body.

The invention therefore relates to the use of a composition comprising:

-   -   a) at least one corticosteroid    -   b) optionally a diluent    -   c) optionally at least one anesthetic solution with or without        vasoconstriction agent    -   d) optionally one component to prevent skin atrophy    -   e) saline or physiological pH solution for producing a        medicament to reduce small areas of subcutaneous accumulations        of fat.

In an alternative and preferred embodiment, the invention relates to theuse of a composition comprising:

-   -   a) at least one corticosteroid    -   b) optionally at least one anesthetic solution with or without        vasoconstriction agent    -   c) optionally one component to prevent skin atrophy    -   d) saline or physiological pH solution for producing a        medicament to reduce small areas of subcutaneous accumulations        of fat.

The invention further relates to the use of a composition comprising:

-   -   a) at least one corticosteroid    -   b) optionally a diluent    -   c) optionally one component to prevent skin atrophy    -   d) saline or physiological pH solution for producing a        medicament to reduce small areas of subcutaneous accumulations        of fat.

In the context of the present invention, the composition may comprisemore than one corticosteroid and for example two or more in combinationin the same physiological medium.

The invention further relates to the use of a composition comprising:

-   -   a) at least two or more corticosteroids    -   b) optionally at least one anesthetic solution and    -   c) saline or physiological pH solution for producing a        medicament for reduce small areas of subcutaneous accumulations        of fat.

The invention further relates to the use of a composition comprising:

-   -   a) at least one or more corticosteroids    -   b) optionally a diluent    -   c) at least one anesthetic solution with or without        vasoconstriction agent    -   d) at least one active ingredient to destroy fat, such as a        phospholipids or deoxicholate    -   e) at least one component to prevent skin atrophy or the spread        of the product    -   f) saline or physiological pH solution        for producing a medicament to reduce small areas of subcutaneous        accumulations of fat.

The invention further relates to the use of a composition comprising:

-   -   a) at least one corticosteroid    -   b) optionally a diluent    -   b) at least one anesthetic solution with or without        vasoconstriction agent    -   c) component assisting degradation of the fat    -   d) at least one component to prevent skin atrophy    -   e) saline or physiological pH solution        for producing a medicament to reduce small areas of subcutaneous        accumulations of fat.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 provides a histologic picture which shows fat tissue withhematoxilyn-eosin stain before treatment and the measurements of someadipocyes in pixels using same magnification.

FIG. 2 provides a histologic picture which shows fat tissue withhematoxilyn-eosin stain after treatment and the measurements of someadipocyes in pixels using same magnification.

FIG. 3 provides a view of an MRI exam performed before a single sessionof treatment with triamcinolone injections.

FIG. 4 provides a view of an MRI exam performed after a single sessionof treatment with triamcinolone injections.

FIG. 5 provides a view of a patient with marked areas for injectiontreatment, before treatment.

FIG. 6 provides a view of the same patient with marked areas forinjection treatment one month after a single session.

FIG. 7 provides a flow chart of an embodiment of the steps involved inthe method of treatment.

DETAILED DESCRIPTION

The invention further relates to the use of the compositions forproducing a medicament for the treatment of small fat accumulations onthe face and body, including residual areas of liposuction and otherlocalized fat accumulation.

The invention further relates to the use of the compositions forproducing a medicament for the treatment of derangements of fatdistribution of an unwanted nature, such as raised areas of celluliteand fat related tumors.

One embodiment of the present invention is a method of decreasing orreducing small fat deposits by administering to an individual in needthereof, a sufficient amount of a composition comprising at least oneinjectable corticosteroid with a physiological acceptable medium. Thesaid may further comprise at least one anesthetic agent and/or at leastone component to prevent skin atrophy. In a preferred embodiment thesaid composition is administered to an individual in need by localinjections in the subcutaneous fatty areas.

By diluent it is meant any acceptable diluent of the injectablecorticosteroid which is preferably 0.9% saline or saline plus anestheticsolution, or anesthetic solution alone. Injectable anesthetic solutionsas diluent are preferable to make the procedure less painful. The mostfrequent anesthetic solutions have lidocaine as the active ingredient,but bupivacaine and others may be used.

In another embodiment of invention, vasoconstriction agents areincorporated to injectable anesthetic solutions and thus help the activeingredient to remain at the injection site and increase the safe dose ofthe anesthetics. The most frequently used vasoconstriction agents areepinephrine and phenylephrine.

By physiological acceptable medium it is meant a medium compatible withintralesional or subcutaneous injection. This medium can be prepared inadvance or in a way that it can be prepared immediately before use.

According to the invention, through the use of the compositions it ispossible to avoid the abovementioned risks and side effects of surgicaltreatments and those arising from injectable lipodissolve agents at thecurrently used doses. In addition, this is a minimally invasive,outpatient treatment, showing great cost-effectiveness.

Contraindications for the use of systemic corticosteroids includediabetes, infectious illness, HIV, psychiatric disorders, SAH and otherspecific conditions.

Studies show that small doses of systemic corticosteroids for shortperiods of time can be considered safe, in patients without the abovecontra-indications. The doses for local injections (e.g.intra-articular, intrabursal, intradermal, intralesional) are given asranges only. A safe dose of Triamcinolone is less than 0.15 mg/kg. Theactual dosage depends upon the size of the joint of lesion and theseverity of the condition being treated.

The safer use of corticosteroids refers to less than 1 week on therecommended doses. Frequent applications and high doses of thesecompounds can cause systemic side-effects. Even small doses, if used forlong periods of time can also cause systemic side-effects.

Although the benefits of glucocorticoid therapy are derived fromshort-term vascular changes and limited immunosuppression, prolonged orhigh-dose glucocorticoid therapy has multiple side effects (PharmacolTher 2002; 96: 23-46). Glucocorticoid treatment can cause hypertensionby two distinct mechanisms: one involves renal sodium retention and theensuing increase in blood volume; a second results from potentiation ofvasopressor responses to angiotensin II and catecholamines (CardiovasRes 1999; 41:55-64). Even inhaled glucocorticoids are absorved by thecirculatory system and still cause side effects such as a decreasedgrowth rate in children (J Allergy Clin Immunol 2003; 112:Suppl3:s1-s40; Arch Inter Med 1999; 159:941-55).

The most known side-effects of the oral and parenteral use ofcorticosteroids are gland adrenal atrophy, cushing's syndrome,dyslipidemia, hypertension, thrombosis, vasculitis, changes in behavior,cognition, memory, and mood (i.e., glucocorticoid-induced psychoses),cerebral atrophy, gastrointestinal bleeding, pancreatitis, peptic ulcer,activation of latent viruses, opportunist infections, delayed woundhealing, erythema, hypertrichosis, perioral dermatitis, petechiae,glucocorticoid-induced acne, striae rubrae distensae, telangiectasia,skin atrophy (including single injections of trancinolone on dose of 10mg or 25 mg hydrocortisone), bone necrosis, muscle atrophy,osteoporosis, retardation of longitudinal bone growth, cataracts,glaucoma delayed puberty, fetal growth retardation, hypogonadism (NewEngland J Med 2005; 353:1711-23; British Journal of Rheumatology 1991;30:39-44).

Recently, a review showed that the side effects of short-term oralcorticosteroids such avascular necrosis and a few cases of fatalvaricella-zoster can occur in immunocompetent patients. Severe moodchanges and psychotic reactions rarely occur unpredictably withshort-term corticosteroids. These events are rare, and most treatmentswith short-term corticosteroid therapies are problem free. Theliterature reviewed clearly indicates that a short course ofcorticosteroids of 1 week, in the absence of specific contraindications,is unlikely to be harmful (psychotic or prepsychotic episodes possiblyexcepted (J Cutan Med Surg. 2008; 12(2):77-81).

Triamcinolone acetonide has been used as intravitreal injection withsome complications like infectious endophthalmitis, transient centralretinal artery occlusion, conjunctival ulcerations, retinal detachmentand potential reactivation of a cytomegalovirus retinitis and posteriorsubcapsular cataract (Ophthalmologe. 2004 February; 101(2):121-8.,Ophtalmol. 2008 September; 31(7):693-8; J Drugs Dermatol. 2008;7(8):757-61). Intralesional triamcinolone acetonide has been usedextensively for the treatment of hypertrophic and keloid scars.Complications are few, usually being local skin color changes, prominentvascular markings, or subcutaneous atrophy. Although, cushing's syndromefollowing intralesional administration of triamcinolone acetate hasalready been described (Ann Plast Surg 1996 May; 36(5):508-11).

The term “intralesional injections” means injections applied into aspecific area, condition or lesion. However, the administration ofcorticosteroids in the context of the invention is preferably carriedout subcutaneously where fat deposits are located in the human faces andbodies.

Not only acetonide but also other forms of Triamcinolone, such ashexacetonide, can be used for parenteral and/or intralesional and/orsubcutaneous injections. Short-acting injectable corticosteroids arepreferable to be use in this medical indication.

Side-effects of intralesional injections of Triancinolone and otherinjectable corticosteroids in dermatology include skin discoloration,skin atrophy and risk of systemic side-effects, when high doses andfrequent injections of this compound are used.

Pariser and Murray described a greater risk of cutaneous atrophy withconcentrations above 5 mg/cm³ of triamcinolone acetonide (Pariser H,Murray P F. Intralesional Injections of Triamcinolone. Effects ofdifferent concentrations on psoriatic lesions. Arch Dermatol. 1963February; 87:183-7).

Injections into the superficial dermis can result in initial epidermalsloughing and persistent epidermal atrophy, whereas those in the deepdermis and subcutis may result in variable loss of fat with minimalepidermal change (Donofrio L M. Panfacil volume restoration with fat.Dermatol Surg 2005; 31: 1496-1505).

Besides skin atrophy, skin side effects arising from intralesionalinjections on the skin and/or subcutis include skin discoloration,asymmetries and volume reductions with consequent sagging of thesuperjacent skin. When the applications are done to the subcutaneousfat, these local side effects are mainly related to superficialinjections. The risks of local side effects, such as skin necrosis andatrophies are rare; local atrophy may be wanted only for the fat tissuebut not to the skin (epidermis and dermis).

The term “local anesthetic” means injectable and/or topical compounds.The Injectable anesthetic compounds are selected from mepivacaine,bupivacaine, ropivacaine; chloroprocaine, procaine,articaine/epinephrine and lidocaine and can be used as a diluent.Topical anesthetic creams or a cooler can be used to reduce the pain ofthe injections.

Local anesthetic solutions can or cannot contain a substance that causesvasoconstriction, such as adrenaline, phenylephrine and others.Vasoconstriction agents added to the anesthetic solution can limit andincrease the local effects and also increase the safe dose of localanesthetics, from 4 to 7 mg/kg of lidocaine.

For the treatment of localized fat, the reasonable average recommendeddose of Triamcinolone diluted in local anesthetic solution is 4 mg permonth for 3 or 4 months.

The compositions of the invention are produced, for example, bydissolving 0.1 mL of Triamcinolone acetonide (40 mg/mL) and 0.2 mL oflidocaine with phenylephrine. It could be possible to add ananti-atrophy or lipodissolve agent.

The solution or dispersion containing the active drug (corticosteroids)is usually concentrated, and then a diluent is added to increase thedilution. In an alternative embodiment, the anesthetic solution is addedas a diluent or in replacement of the diluent to increase the dilutionand make the treatment more confortable for the patients. Production ofthe compositions of the invention are usually done at the moment ofapplication.

Alternatively, the solution or dispersion containing the active drug(corticosteroids) is in a proper safe dose and appropriately diluted andit is at the physician's discretion to add or not to add the anestheticsolution.

Simultaneous introduction of the compositions and pharmaceutical formsemployed according to the invention can also take place in particularapplications via tumescence method which makes use of the hydrostaticpressure in order to ensure uniform distribution and to increase thesafety and efficacy of the procedure. These can be achieved bydissolving the preparations of the invention in higher volumes of salineand/or other necessary pharmacological agents. Variations on thetechnique can also be done, by preceding the injection of the activedrug (triamcinolone or similar) by local tumescent anesthesia.

In the context of the present invention, additional ingredients can beadded to the formulation.

The composition(s) employed according to the invention, and comparablepharmaceutical forms, are administered by subcutaneous injections on thefat, also called “local” or “intralesional” injections. Subcutaneousinjections at deep level is preferred for cosmetic lipoatrophy.

Suitable preparations and pharmaceutical forms can be suspensions,emulsions or injectable solutions, and products with protracted releaseof active ingredients. In order to increase the stability of thecompositions and pharmaceutical forms of the invention, the preparationscan also be in the form of a concentrate, dry substance orlyophilizates.

These pharmaceutical products are preferably produced and administeredin dosage units, each unit comprising a particular dose of thecomposition(s) as active ingredient. In the case of solutions forinjection in ampoule form, this dose can be adjusted, preferably fromabout 3 mg to 10 mg of Triancinolone acetonide, or equivalent doses ofother injectable corticosteroids.

Monthly doses of solutions for injection required for the treatment ofan adult patient are, depending on the size of the treated adiposetissue, from 3 mg to 10 mg, preferably 3 mg to 5 mg of Triancinoloneacetonide, or equivalent doses of other injectable corticosteroids.

Suitable preparations and pharmaceutical forms to be injected can alsobe diluted before administration, preferably with saline solution.However, in some circumstances, higher or lower monthly doses may alsobe appropriate. The dose also depends on the area to be treated, thedisease, condition or amount and/or thickness of the fat tissue to betreated

Administration of the monthly dose can take place both through a singledose in the form of a single dosage unit or else a plurality of smalldosages units and by multiple dosages of divided doses at definedintervals.

The term “subcutaneous derangements of fat distribution” means adiposetissues in the body of humans and animals which occur as geneticallyrelated or food-related depot of fat in the form of localized fat padsand can be regarded as esthetically disturbing critical zones such asabdomen, buttocks, hips, knee, calves, thighs, upper arm, chin, cheeks.They may also involve dystrophic proliferations of adipocytes such asbenign proliferations of the fat cells like that occurring in lipomas.

The term “small localized area of fat accumulation” means all areas from10 cm3 to 30 cm³ of fat localized on the face or body that occurred dueto an increase in the number or size of the fat cells. These includeperibucal, eyebulging, submandibular, preaxillary fat, small raisedareas in the abdomen and/or dorsum, love handles, raised areas on thebuttocks, as well as excess response from surgical procedures such asliposuction and Subcision. These are usually considered cosmeticdefects.

The term “adipocyte's atrophy” means decrease in the size and/or numberof adipocytes as shown by skin biopsies. This adipocytes' atrophy leadsto reduction of the treated small localized fat deposits.

Due to the extensive knowledge and published data, Triamcinolone and itsderivatives, as well as other parenteral corticosteroids, are consideredvery safe. This patent reported a new potential use of local injectionsof triamcinolone, also called “local” or “intralesional injections”, toinduce cosmetic lipoatrophy of small localized fat deposits by reducingthe size of the adipocites and fat tickness. This is a fast, efficient,cost-effective and low risk procedure, useful for cosmetic proposes.

Turning now to FIG. 1, a histologic picture is provided which shows fattissue with hematoxilyn-eosin stain before treatment and themeasurements of some adipocyes in pixels using same magnification.

FIG. 2 is an histologic picture which shows a sample of fat tissue ofthe same area as FIG. 1, resulting from skin biopsy one month aftersingle treatment with Triamcinolone local injections. There is areduction on the average of the diameter of the adipocytes in thetreated area.

FIGS. 1 and 2 show morphometry performed at the biopsies of thesuprapubical area treated with a single injection of triamcinolone,before (FIG. 1) and one month after (FIG. 2). The average number ofadipocytes observed in the optical field at the same magnificationincreased from 4 to 7 adipocytes per field. The average area of theadipocytes reduced from 31661 to 21705 pixels and their averagediameters reduced from 190 to 153 pixels.

FIGS. 3 and 4 refer to MRI exams performed before (FIG. 3) and after(FIG. 4) single session of treatment with triamcinolone injections.There was a reduction of 27.3% of the thickness of the study area offacial fat before (1.1 cm) and after (0.8 cm) treatment.

FIGS. 5 and 6 show the same patient with marked areas for TA injections,before (FIG. 5) and one month after (FIG. 6) single session of TAinjections.

FIG. 7 provides a flow chart of steps involved in an embodiment oftreatment. The treatment begins by identifying a small fat deposit or anumber of fat deposits to be reduced by treatment. The size of thesedeposits may be then determined. Next, an amount of corticosteroid isdetermined to reduce the size of the identified fat deposits. Oncedetermined, a composition is injected into the fat deposit, thecomposition comprising the determined amount of corticosteroid, andoptionally other components as described herein. This process may berepeated, for example, monthly, to maintain reduction of the fatdeposits.

The present invention is described by the following example which is oneof several embodiments.

Example

A retrospective sample of treated patients is presented with theobjective to describe a new therapeutic modality to treat smalllocalized fat areas of the face, which interfere with youth and beautyof the face. Moreover, there is the need for minimally invasivetreatment to safely treat small areas of localized fat on the face.

Research Design and Methods

A series of cases of small localized fat deposits on the face weretreated with local triancinolone from March 2005 to October 2008 at aprivate clinic in Porto Alegre, southern of Brazil. Fifty six femalepatients with localized fat areas of the face were included in thissample. They received injections of triamcinolone (Kenalog®-40Injection) diluted in anesthetic solution (0.02 g/mL Lidocaine plus0,0004 g/mL Phenylephrine—Novocol®), in different concentrations andnumber of applications (up to 3 injections, once a month), according topatient's needs. The areas treated were mandibular and submental area,and, the inferior eyelids. Patients received injections in these fattyareas of the face, through a 0.3 cc BD Ultra Fine II syringe with shortneedle. All the injections were performed at the subcutaneous, 4 to 7 mmbelow the cutaneous surface. Small volumes (0.01 to 0.02) of the dilutedtriamcinolone were injected at 1 cm apart at the treated areas.

One patient was submitted to a facial Magnetic Resonance Imaging (MRI)exam before and after the triamcinolone injections, in order to show theresults in terms of the changes in the thickness of subcutaneous tissue.Magnetic resonance imaging examination was performed with 1.5 TeslaClosed Bore Scanner (Magnetom Symphony Maestro Class, Siemens, Erlangen,Germany) with dedicated flexible coils. T1-weighted (600 ms/14 ms, TimeRepetition/Time Echo) and T2-weighted (2500 ms/45 ms, TR/TE) turbo spinecho sequences were performed in coronal, axial and sagittal planes,with emphasis on the sagittal plane. An experienced radiologistevaluated the MRI images. The thickness of SQ adipose tissue wasmeasured with Syngo software (Siemens, Erlangen, Germany) in millimeters(mm).

Another patient was submitted to 3 mm punch biopsies (one on thesubmental area and another on suprapubical area) before and after singletreatment.

Histological specimens of SQ tissue was stained with hematoxylin andeosin (HE stain) and also flow citometry was also performed in thehistological images of before and after treatment samples.

Medical records included the main surgical cosmetic procedures carriedout in association with triamcinolone injections, at the privatedermatological clinic where the study took place.

The records of 56 patients with localized fat areas on the face thatwere treated with triamcinolone injections diluted in an anestheticcommercial composition were reviewed retrospectively. All patients wereCaucasians women and the average of age was 57, 2±12, 2 years.Demographic data and characteristics of the triamcinolone applicationswere obtained from the clinical files, highlighting the main applicationareas, the dilution of the drug and the number of sessions. These datais presented in Table 1.

TABLE 1 Average of Proportion Average Average of volume of of dosevolume (mL) Anesthetic triamcinolone: Number (mg) of administeredsolution in and of Age triamcinolone of diluted the Anesthetic Groupssubjects (years) (per session) triamcinolone composition solutionMandibular Area 37 59 ± 12 5.2 0.13 0.27 1:2.1 Submental Area 11 52 ± 084.8 0.12 0.2  1:1.7 Inferior Eyelids  8 55 ± 16 3.2 0.08 0.16 1:2   Agewas described in average ± Standard deviation.

Regarding the frequency of injections, they were performed as follow:one session for submental area; one or two sessions for infraorbitalarea (62.5% of this group of patients were submitted to one session,whereas 37.5% were submitted to two sessions); one to three sessions forthe mandibular area (70.3% of this group of patients were submitted toone session, 27% were submitted to two sessions, and only 2.7% weresubmitted to three sessions).

Fifty seven percent of the patients underwent to another cosmeticprocedure performed in the same day and surgical session. These patientsreceived the triamcinolone injections and 30.3% received also fillers;16% received also Botulinum Toxin (BT) and 10.71% received both (fillersand BT) combined with the Triamcinolone injections.

Twenty nine subjects (51.78%) returned to the clinic for evaluation. Allof them were very satisfied with the results of the procedure and didnot presented serious adverse events. The physician who evaluated thesesubjects considered that they had good clinical and cosmetic improvementof facial contour due to reduction of the fatty areas, as shown in thebefore and after figures (FIGS. 4 and 5). Twenty seven patients have notreturned for evaluation yet, so subject satisfaction and clinicalimprovement are missing.

High resolution MRI images performed in the axial plane demonstratedthat there was significant reduction of the SQ adipose tissue at thetreated area (mandibular). The reduction of the fat tickness showed byMRI was 37.5% at the mandibular area (from 0.8 to 0.5 cm) and 33.3% atthe submental area (from 0.6 to 0.4 cm) (FIGS. 3 and 4)

Histological analysis demonstrated about 30% reduction in the volume ofadipocytes in the sites of the injections, as shown in the before andafter single treatment biopsies. Flow citometry results showed reductionin the average of the diameters of the adipocytes increase of the numberof the adipocytes that were visualized per field at the samemagnification field (from 4 to 7). (FIGS. 1 and 2)

A few local side-effects were observed in this group of the patients.The majority of the patients had pain and slight erythema during andimmediately after the injections. Many patients presented hematomas invariable number and size, which disappeared spontaneously in a few days.No severe local or systemic side effects were observed in the patientstreated with this new technique. No lab exams were done to evaluatepotential systemic absorption of the drugs.

Cosmetic local side effects were presented by three patients, asdescribed below:

-   -   one case of skin relief depression in the lower eyelid that        appeared 2 months after the injection. No treatment was given        and it disappeared after 1 months;    -   one case of skin and subcutaneous atrophies, caused by        accidental superficial injections. This happened due to        continuous talking by the patient during injections at the        mandibular area. This was corrected with small volumes of an        hyaluronic acid filler injections (Restylane—Q-Med);    -   one case of increased laxity of the mandibular skin was noted,        although this patient never complained about this. This can be        treated by radiofrequency of Infra-red light;    -   one case of asymmetry of the anterior fatty areas of neck. This        was corrected with a second session of triancinolone injections.    -   Sub-optimal response may also occur.

There is indication for a few monthly injections of the composition, dueto the risk of systemic effects of corticosteroids.

CONCLUSION

The subcutaneous fat face is partitioned into discrete anatomiccompartments: nasolabial fat, cheek fat, forehead and temporal fat,orbital fat and jowl fat.

A youthful face is characterized by the fullness and by a smoothtransition between subcutaneous compartments. Facial aging is, in part,characterized by how these compartments change with age. Aging leads toabrupt contour changes between these regions, by volume loss andmalposition of these compartments, in a number of causes¹¹. A youth facelooks like a triangle with its base up. In aged face, fat accumulationaround the mandibular bone looks like a triangle with the base down.

Rare studies address solutions for the aged related facial fat deposits,which are a frequent complaint, and increase skin sagging. They usuallyare seeking for surgical procedures to correct these problems. (HexselD, Serra M, Mazzuco R, Dal'Forno T, Zechmeister D. J Drugs Dermatol.2003 October; 2(5):511-8; Rotunda A M, Kolodney M S. Dermatol Surg.2006; 32(4):465-80)

Small doses of triamcinolone in intralesional and local injections arelargely used in dermatology for the treatment of many skin conditions,such as keloids and others. Due to the extensive knowledge and publisheddata, intralesional injections of triamcinolone are considered verysafe.

Intralesional corticosteroids injections release a high concentration ofthe drug directly on the action site, with minimal systemic absorption(Firozz, 1995) Among the many corticosteroids used for injections,triamcinolone and derivatives are more commonly used in dermatology(Firozz, 1995) and triamcinolone is the more acceptable due to itsphysical characteristics (Callen, 1981).

This patent application reports a new potential use of this drug inintralesional and local injections, to induce cosmetic lipoatrophy ofthe face by reducing the size of the adipocytes as well as in the fattickness.

This is a fast, efficient, cost-effective and low risk minimallyinvasive procedure, useful for cosmetic proposes.

The invention claimed is:
 1. A method of causing fat cell atrophy bydecreasing the size of a small fat deposit comprising the steps of:identifying a small fat deposit of an individual to be decreased; andadministering, to the individual, an amount of an injectable compositioncomprising a corticosteroid and a physiological acceptable medium; saidamount sufficient to cause a decrease in the size of the small fatdeposit; wherein the step of administering comprises injecting asufficient amount of the composition, using a needle, into the small fatdeposit of the individual, to cause a decrease in the size of the smallfat deposit; wherein the composition comprises 0.1 mL of triamcinoloneacetonide at a concentration of 40 mg/mL as the corticosteroid; 0.2 mLof a solution of 0.02 g/mL of lidocaine; and a vasoconstriction agentselected from the group consisting of phenylephrine or epinephrine; in asaline or physiological pH solution as the physiological acceptablemedium.
 2. The method of claim 1 wherein the step of administering thecomposition is performed by injecting the composition into the small fatdeposit on the face of the individual.
 3. The method of claim 1 whereinthe step of administering the composition is performed after a step ofremoving a large fat deposit by liposuction.
 4. The method of claim 1wherein the step of administering the composition is performed by asubcutaneous injection.
 5. The method of claim 1 wherein the step ofadministering the composition is performed by an intralesionalinjection.
 6. The method of claim 1 wherein the administration step isrepeated every month.
 7. The method of claim 1 wherein the size of thesmall fat deposit is between 15 cubic centimeters and 30 cubiccentimeters.
 8. The method of claim 1 wherein the step of administeringthe composition results in a localized concentration of the composition.9. The method of claim 1 wherein the composition further comprises anactive ingredient to destroy fat cells, the active ingredient being atleast one of phospholipids and deoxycholate.
 10. The method of claim 1further comprising the steps of: determining a size of the small fatdeposit; determining a dosage of corticosteroid in the compositionrequired to reduce the size of the small fat deposit; and administeringa dose of corticosteroid of less than 4 mg and greater than or equal to3 mg.
 11. The method of claim 1 further comprising the steps ofdetermining a size of the small fat deposit; determining a dosage ofcorticosteroid required to reduce the size of the small fat deposit;selecting a solution containing the corticosteroid; and diluting thesolution with the physiological acceptable medium to form thecomposition.
 12. The method of claim 1 wherein the vasoconstrictionagent is phenylephrine and is added to the composition as a solution ina concentration of 0.0004 g/mL.
 13. A method of causing fat cell atrophyby decreasing the size of a small fat deposit comprising the steps of:identifying a small fat deposit of an individual to be decreased; andadministering, to the individual, an amount of injectable componentscomprising a corticosteroid and a physiological acceptable medium; saidamount sufficient to cause a decrease in the size of the small fatdeposit; wherein the step of administering comprises injecting asufficient amount of the components, using at least one needle, into thesmall fat deposit of the individual; wherein the administering stepcomprises forming a composition within the small fat deposit throughmore than one injection; wherein the composition comprises 0.1 mL oftriamcinolone acetonide at a concentration of 40 mg/mL as thecorticosteroid; 0.2 mL of a solution of 0.02 g/mL of lidocaine; and avasoconstriction agent selected from the group consisting ofphenylephrine or epinephrine; in a saline or physiological pH solutionas the physiological acceptable medium.
 14. The method of claim 13wherein the vasoconstriction agent is phenylephrine and is added to thecomposition as a solution in a concentration of 0.0004 g/mL.